Abstract Details

Title Expanded Phenotype of GFPT1-related Disorder is a Mimicker of Mitochondrial Leukoencephalopathy

Topic Child Neurology and Developmental Neurology

Presentation(s) P4 - Poster Session 4 (5:30 PM-6:30 PM)

Poster/Presentation
Number 7-049

Objective

We sought to determine the molecular etiology of disease in four individuals from two unrelated families who presented with proximal muscle weakness and clinical features suggestive of mitochondrial disease.

Background

Next-generation sequencing has provided significant advantages in the diagnosis of disorders disrupting energy metabolism.

Design/Methods Clinical information and neuroimaging were reviewed. Genome sequencing was performed on affected individuals and biological parents.

Results All affected individuals presented with muscle weakness and difficulty walking. In one family, both children had neonatal respiratory distress while the other family had two children with episodic deteriorations. In each family, muscle biopsy demonstrated ragged red fibers. MRI was suggestive of a mitochondrial leukoencephalopathy, with extensive T₂ hyperintense signal deep in the cerebral white matter and selective involvement of the middle blade of the corpus callosum. Genome sequencing identified homozygous GFPT1 missense variants in the affected individuals of each family. GFPT1 variants cause a congenital disorder of glycosylation manifesting in a congenital myasthenia syndrome. The variants detected (p.Arg14Leu and p.Thr151Lys) are absent from the GnomAD population database, encode highly conserved amino acids and are predicted damaging by in silico prediction tools. Nerve conduction studies were performed following genetic diagnosis, and demonstrated a decremental response to repetitive nerve stimulation, confirming the diagnosis of myasthenia. Treatment with pyridostigmine was started in one family with favorable response.

Conclusions GFPT1 encodes a widely expressed protein that controls the flux of glucose into the hexosamine-biosynthesis (HBP) pathway that produces precursors for glycosylation of proteins. Mitochondria are targets for O-GlcNAcylation, and are glycosylated in settings of acute stress, providing resistance to stress provoked reactive oxygen species and mitochondrial dysfunction and suggest that diminished mitochondrial health could contribute to this disorder. These findings identify leukoencephalopathy as a previously unrecognized phenotype in GFPT1-related disease and allowed meaningful change in management, with implications for their health and quality of life.

Authors/Disclosures
Guy T. Helman PRESENTER	No disclosure on file
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Marjo Van Der Knaap, MD, PhD (VU University Medical Center)	The institution of Marjo Van Der Knaap, MD, PhD has received research support from Calico. The institution of Marjo Van Der Knaap, MD, PhD has received research support from Ionis.
	No disclosure on file

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